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Secondary Findings in Cancer Patients Spur Dutch Team to Rethink Consent, Reporting Options


NEW YORK (GenomeWeb) – Unsolicited germline results from tumor sequencing tests present challenges unique to the cancer field, researchers in the Netherlands have found, prompting them to make changes to their pre-testing counseling, informed consent, and reporting process.

In a paper published in the European Journal of Human Genetics last week, the researchers, from the Center for Personalized Cancer Treatment (CPCT), a Dutch consortium of cancer centers, reported on their experience with returning unsolicited results — also called secondary or incidental findings — highlighting the importance of pre-test patient education and having a policy to disclose test results to family members.

CPCT was founded in 2010 by the three largest cancer centers in the Netherlands — University Medical Center Utrecht, Erasmus MC/Daniel den Hoed Clinic in Rotterdam, and the Netherlands Cancer Institute in Amsterdam — with the mission to improve cancer treatment outcomes and patient care. In the meantime, the consortium has grown to include a total of eight university hospitals and more than 10 large teaching hospitals in the Netherlands.

Patients with metastatic cancer who are treated at any of these hospitals can have a biopsy of their tumor and germline DNA from their blood sequenced through CPCT. Based on the molecular profile of their tumor, they can subsequently enroll in various clinical studies, but their data is also used for research.  

Generally, a patient is referred to a CPCT investigator by his or her treating oncologist, who informs the patient about the goal of CPCT's research, the biopsy procedure involved, and the possibility of unsolicited findings of an increased genetic disease risk. After providing written informed consent, the patient provides samples for sequencing.

Prior to 2014, the researchers noted, patients could opt out of receiving unsolicited findings, but that changed when the research ethics committee made the return of clinically relevant and actionable unsolicited findings mandatory, so patients could no longer enroll without consenting to obtaining such results.

Last year, CPCT teamed up with the Hartwig Medical Foundation, which established a centralized national sequencing facility in Amsterdam that is equipped with Illumina's X Ten platform. According to Rhodé Bijlsma, an oncologist at UMC Utrecht and the lead author of the EJHG paper, the new center has been conducting all sequencing for CPCT since February, performing whole-genome sequencing. While much of that data is being used for research purposes, clinical reporting focuses on 50 cancer-related genes that are based on the Ion Torrent AmpliSeq Cancer Hotspot Panel that the CPCT previously used.

Variant interpretation and reporting involves a team of bioinformaticians, pathologists, medical oncologists, molecular geneticists, and clinical geneticists. The report — including secondary findings — goes to the treating oncologist, who informs the patient. Those with incidental findings are also referred to a clinical geneticist for additional counseling and to verify the result in a second blood sample.

Between 2011 and mid-2015, CPCT took tumor biopsies and blood samples from more than 600 late-stage cancer patients and performed next-gen sequencing on more than 370 of them, a number that has increased to about 460 by now, Bijlsma said. Three patients so far had secondary findings of genetic risk factors. "It's not a lot, but there is a small possibility that patients are confronted with these unsolicited findings," Bijlsma said.

One patient with ovarian cancer had a germline deletion in BRCA2 and decided to inform her family members about the result. The second patient, with breast cancer, had a germline mutation in a gene associated with a melanoma syndrome but did not attend her appointment with a clinical geneticist, even though the result would be highly relevant to her family members. The third patient, who had melanoma, had a variant of unknown significance in BRCA2 but died before the test results were available.

Based in part on these cases, the researchers are now planning to make changes to the testing process. Part of it is to provide better pre-test and pre-informed consent education, Bijlsma said, so when a secondary finding arises, they have a better understanding of what it means and how it may affect family members. "We experience that patients have a lot of problems understanding this next-generation sequencing. It's a really difficult topic for patients," she said. The example of the second patient in particular "brought to our attention that a patient needs to be counseled more than in the past."

Ideally, patients would see a geneticist prior to testing, but that will probably not be financially sustainable, she said. In lieu, patients may be offered educational videos, brochures, or questionnaires to fill out with their doctor or at home.

The researchers are also trying to figure out a process to contact family members if a patient dies before unsolicited germline results become available, if this was the wish of the patient. For this, they need to consider who the point of contact will be and whether a family member or the doctor needs to initiate the process.

Finally, they want to reverse the informed consent policy of giving patients no opt-out for unsolicited findings, and move to a layered inform consent instead that lets them decide between different categories of results they would like to receive. These categories could be, for example, results relating to preventable or treatable diseases, variants for untreatable diseases, carrier mutations, and variants of uncertain significance.

Bijlsma said her team has already conducted a qualitative study of 24 patients, asking them about their opinions on these categories. "Patients at first always say, 'I would like to be informed about everything because it's my material, my body, my information,'" she said. "But when you give them more information about unsolicited findings and their possible impact, patients get a little bit cautious" and decide they only want certain categories and not others.

CPCT is not the only group to develop strategies for pre-test counseling and reporting of secondary germline findings to cancer patients. Memorial Sloan-Kettering Cancer Center in New York, for example, started optional reporting of pathogenic germline variants detected by its MSK-IMPACT test about a year ago.

Last November, a team from MSKCC reported that of almost 1,600 late-stage cancer patients analyzed, almost 250, or 16 percent, had pathogenic germline variants in one of 187 genes.

Michael Berger, a researcher at MSKCC who co-developed the test, told GenomeWeb this week that prior to providing informed consent for the germline analysis, patients watch an informational video on an iPad in their oncology clinic that describes the implications of the test.

Patients can then either opt in to receive these results or opt out. The current test, which is for patients who have their tumor profiled but don't necessarily have a family history of cancer, reports all pathogenic germline variants found in about 80 genes.

The informed consent for the germline analysis also includes a section where the patient can designate someone else to receive incidental results from his or her test.